摘要
该文概述了近10年来有关药物中基因毒性杂质监管指南的完善历程与相关检测方法的研究进展。介绍了基因毒性杂质从早期的完全避免到目前的阶段化毒理学关注阈值(TTC)的风险控制理念以及各主流监管机构的具体要求。作为一类重要的基因毒性杂质,磺酸酯主要来源于磺酸及衍生物与低级醇(如甲醇、乙醇、异丙醇等)之间发生的副反应,具有化学结构类型多样化的特点。该文较为详尽地介绍了磺酸酯的形成机理和文献所采用的液相色谱法和气相色谱法,并对色谱方法的选择、预处理方式、衍生化方法及相应痕量水平的灵敏度和回收率等进行了评述。由此期望为合理控制药物中磺酸酯类基因毒性杂质,为保证药物的质量安全性提供有益的指导意见。
This article reviews the refinement of regulatory guidelines and progress of research on the control of genotoxic impurities in pharmaceuticals in the last decade. It outlines advances in the regulatory requirements for genotoxic impurities from strict avoidance to the currently accepted concept of threshold of toxicological concern （TTC）, which is based on risk control considerations. Specific control limits, which are required by predominant administrative regulatory agencies, such as U. S. Food and Drug Administration （FDA）, European Medicines Agency （EMA） and the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use （ICH）, etc. Sulfonate esters, an important class of potential genotoxic impurities, are usually generated by side-reactions between sulfonic acids or their derivatives and relative low molecular mass alcohols, such as methanol, ethanol, and isopropanol. The resulting sulfonate esters are characterized with diverse chemical structures. Reaction mechanisms of the formation of sulfonate esters and various strategies to control them have been schematically described. A detailed summary has been given for the analytical methodology developed using high performance liquid chromatography （HPLC） and gas chromatography （GC） to determine trace amounts of sulfonate esters in pharmaceuticals. Furthermore, we have comprehensively discussed the options for the chromatographic methods, sample pretreatments, and derivatization methods, as well as each method＇s sensitivity and recovery at trace level. This review intended to provide constructive suggestions for the rational control of sulfonate esters in pharmaceuticals to ensure their clinical safety.
作者
刘雪薇
厉程
韩海云
张文鹏
陈东英
LIU Xuewei;LI Cheng;HAN Haiyun;ZHANG Wenpeng;CHEN Dongying(Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Shanghai Center for Drug Evaluation and Inspection,Shanghai 201203,China)
出处
《色谱》
CAS
CSCD
北大核心
2018年第10期952-961,共10页
Chinese Journal of Chromatography
基金
中国科学院药物创新研究院自主部署科研项目(CASIMM0120163011)~~
关键词
基因毒性杂质
磺酸酯
控制策略
色谱方法
综述
genotoxic impurity
sulfonate ester
control strategy
chromatographic method
review
